The current study examined whether a postretrieval drug memory could be disrupted by the beta-adrenoceptor antagonist propranolol, administered following reactivation in a cocaine-mediated conditioned place preference paradigm. Following cocaine conditioning, rats were given a test of conditioned place preference, followed immediately by intraperitoneal administration of propranolol or saline. Rats that received propranolol following the preference test showed no preference for the cocaine-paired floor during a subsequent test, while vehicle-treated rats continued to express a preference for the cocaine-paired floor. These deficits in behavior were specific to retrieval of the cocaine-mediated memory, suggesting that postretrieval propranolol induced an impairment of drug-seeking behavior that is consistent with the disruption of a reconsolidation phase following retrieval.

Previous work has demonstrated post-retrieval impairment in associative learning paradigms, including those mediated by drugs of abuse, using nonspecific b-adrenergic receptor (b-AR) antagonists. Remarkably little is known about the role of the specific b-AR subtypes, or other adrenergic receptors, in these effects. The current study examined the effects of b 1 and b 2 , as well as a 1 -adrenergic receptor antagonism following retrieval of a cocaine conditioned place preference (CPP). We found that rats administered the b 2 antagonist ICI 118,551 (8 mg/kg intraperitoneal [IP]) or the a 1 antagonist prazosin (1 mg/kg IP) following a drug-free test for CPP showed attenuated preference during a subsequent test, while the b 1 antagonist betaxolol (5 or 10 mg/kg IP) and a lower dose of prazosin (0.3 mg/kg IP) had no effect. Furthermore, posttest microinfusion of ICI 118,551 (6 nmol/side) or prazosin (0.5 nmol/side) into the basolateral amygdala (BLA) also impaired a subsequent preference. Systemic or intra-BLA ICI 118,551 or prazosin administered to rats in their home cages, in the absence of a preference test, had no effect on CPP 24 h later. ICI 118,551 also attenuated the FOS response in the BLA induced by the CPP test. These results are the first to demonstrate a role for a 1 -and b 2 -specific adrenergic mechanisms in post-retrieval memory processes. These systemic and site-specific injections, as well as the FOS immunohistochemical analyses, implicate the importance of specific noradrenergic signaling mechanisms within the BLA in post-retrieval plasticity.

Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction.DOI: http://dx.doi.org/10.7554/eLife.17111.001